Abstract
Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Albumins / genetics
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Albumins / metabolism
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Animals
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Antimicrobial Cationic Peptides / genetics
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Antimicrobial Cationic Peptides / metabolism
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Base Sequence
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Cation Transport Proteins / metabolism
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Down-Regulation
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Gene Deletion
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Hepcidins
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Homeostasis / drug effects*
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Humans
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Hypoxia-Inducible Factor 1 / deficiency
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / metabolism*
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Integrases / genetics
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Integrases / metabolism
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Iron / pharmacology*
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Molecular Sequence Data
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Polycythemia / genetics
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Polycythemia / metabolism
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Polycythemia / pathology
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Promoter Regions, Genetic / genetics
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Protein Binding
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Up-Regulation
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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Albumins
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Antimicrobial Cationic Peptides
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Cation Transport Proteins
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HAMP protein, human
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Hamp protein, mouse
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Hepcidins
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Hypoxia-Inducible Factor 1
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metal transporting protein 1
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Iron
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Von Hippel-Lindau Tumor Suppressor Protein
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Cre recombinase
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Integrases